EP0880526B1 - Heterocycle-condensed morphinoid derivatives (ii) - Google Patents

Heterocycle-condensed morphinoid derivatives (ii) Download PDF

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Publication number
EP0880526B1
EP0880526B1 EP97901009A EP97901009A EP0880526B1 EP 0880526 B1 EP0880526 B1 EP 0880526B1 EP 97901009 A EP97901009 A EP 97901009A EP 97901009 A EP97901009 A EP 97901009A EP 0880526 B1 EP0880526 B1 EP 0880526B1
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EP
European Patent Office
Prior art keywords
hexahydro
pyrrolo
methoxy
methanobenzofuro
dimethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP97901009A
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German (de)
French (fr)
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EP0880526A1 (en
Inventor
Giulio Dondio
Silvano Ronzoni
Pier Andrea Gatti
Davide Graziani
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GlaxoSmithKline SpA
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GlaxoSmithKline SpA
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Priority claimed from IT96MI000029 external-priority patent/IT1282950B1/en
Priority claimed from IT96MI002291 external-priority patent/IT1287130B1/en
Application filed by GlaxoSmithKline SpA filed Critical GlaxoSmithKline SpA
Publication of EP0880526A1 publication Critical patent/EP0880526A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0838—Compounds with one or more Si-O-Si sequences
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0896—Compounds with a Si-H linkage
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    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/48—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule in which at least two but not all the silicon atoms are connected by linkages other than oxygen atoms
    • C08G77/50—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule in which at least two but not all the silicon atoms are connected by linkages other than oxygen atoms by carbon linkages
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    • C08K5/00—Use of organic ingredients
    • C08K5/54—Silicon-containing compounds
    • C08K5/541—Silicon-containing compounds containing oxygen
    • C08K5/5415—Silicon-containing compounds containing oxygen containing at least one Si—O bond
    • C08K5/5419—Silicon-containing compounds containing oxygen containing at least one Si—O bond containing at least one Si—C bond
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    • C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
    • C08L83/04—Polysiloxanes
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Definitions

  • the present invention is concerned with novel morphinoid compounds, processes for their preparation and their use in medicine.
  • WO 94/07896 discloses indole-condensed morphinoid compounds useful as immunosuppressants, anti-allergic and anti-inflammatory agents.
  • R 4 and R 5 are hydrogen, hydroxy, acetyloxy, methoxy, O-phenyl, together as an oxy group or R 4 together with R 3 is a methylendioxy group.
  • R 8 is hydrogen.
  • Particularly preferred compounds of formula (I) are those in which R 6 is CONEt 2 , CON(i-Pr) 2 or COO-i-Bu, R 7 is methyl, and R 9 is hydrogen, methyl or CH 2 COOH.
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • conventional pharmaceutical acids for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • the compounds of formula (I) may exists in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.
  • the compounds of formula (I), or salts or solvates thereof may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing reactions not involving racemization processes or it may be prepared by chiral synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of diastereomeric salts by fractional crystallization and subsequent recovery of the pure enantiomers.
  • the compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from the appropriate solvent
  • hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • compounds of formula (I) acting as selective delta receptor ligands may be useful as analgesics, immunosuppressants to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agents, brain cell protectant, for the treatment of drug and alcohol abuse, to decrease gastric secretion, for the treatment of diarrhoea, cardiovascular and respiratory diseases, cough and respiratory depression, mental illness, epileptic seizures and other neurologic disorders (herein after referred to as 'Conditions').
  • the activity of the compounds of formula (I) as delta agonists in standard tests indicates that they are of potential therapeutic utility as analgesic agents for the amelioration or elimination of pain.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Conditions.
  • Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
  • the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinyl-pyrrolidone
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colour
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the compounds of this invention may also be administered by inhalation, via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles.
  • the compound particle size is from about 2 to 10 microns.
  • a further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the activity of the compounds of the present invention as selective delta ligands is determined in radioligand binding assays as described below.
  • Mouse brain membranes were prepared as described by Kosterlitz ( Br. J. Pharmacol. , 1981, 73 , 939.).
  • the binding of the preferential delta ligand [ 3 H]-[D-Ala 2 ,D-Leu 5 ]-enkephalin (DADLE) was evaluated at its K D concentration (1.3 nM) in presence of 40 nM of the unlabelled mu ligand [D-Ala 2 , MePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO).
  • the binding of the mu ligand [ 3 H]-DAMGO Eur. J. Pharmacol.
  • the delta agonist/antagonist activity of the compounds of the present invention is determined in the cAMP bioassay in NG108-15 cell lines as described below.
  • NG 108-15 cell were grown at 37 °C in humidified atmosphere of 5% CO 2 and 95% air in DMEM (without sodium pyruvate using 4500 mg/l glucose) supplemented with 10% foetal calf serum containing 2mM glutamine, 2% HATx50 supplement, 50 ⁇ g streptomycin and 50 I.U. penicillin per ml confluent cells were harvested with 1M EDTA in Ca/Mg-free phosphate-buffered saline with mechanical stirring. Medium was replaced every 2 day. One day before the experiment the cells were dispensed in 17 mm culture plate (about 10x10 6 cells/plate).
  • the growth medium was removed and cells washed twice with a modified Krebs-Ringer medium buffered with hepes-NaOH 200 mM, pH 7.4, that contained (mmol/l): NaCl (125), KCl (5), KH 2 PO 4 (0.4), MgSO 4 and CaCl 2 (1.2) NaHCO 3 (25), glucose (12).
  • Incubation medium was also including 1mM 3-isobuthyl-1-methylxantine (IBMX). Experiments were performed at room temperature. After incubation for 10 minutes to allow IBMX incorporation, NG108-15 cells were exposed to 1 ⁇ M forskolin and the compound to be tested, for 10 minutes. The reaction was terminated by adding cold 0.4N HClO 4 .
  • the most potent compounds described in the present invention showed affinities for the delta receptor ranging from 0.5 to 200 nM with delta selectivity ranging from 20 to 1500 times in respect to the other opioid receptor types. These compounds displayed also potent delta agonist or antagonist properties in the cAMP inhibition bioassay.
  • Selective delta agonists (antagonised by the selective delta antagonist naltrindole) displayed IC 50 s ranging from 1 to 500 nM.
  • MAC Mouse abdominal constriction
  • MTF mouse tail-flick
  • MTF-WW mouse tail-flick warm water
  • the following preparations 1 to 7 illustrate the synthetic procedure to obtain new ketones of general formula (II) that, as such, form a part of the present invention.
  • 4,5-epoxy-17-methyl-3-vinylmorphinan-6-one, 4,5-epoxy-3-(1-ethoxyvinyl)-17-methylmorphinan-6-one, 4,5-epoxy-3-ethyl-17-methylmorphinan-6-one, 3-bromo-4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one and 3-bromo-4,5-epoxy-17-methylmorphinan-6-one are novel compounds and are utilised as starting materials to prepare the compounds of Examples 28, 30, 33, 35, 41, 52, 61 and 64.
  • Preparation 8 illustrates the preparation of a new phosphonohydrazone of general formula (III) that was used as starting material to prepare the compound of Example 89.
  • Example 1 illustrates the preparation of compounds of general formula (I) of the present invention starting from the corresponding ketones of general formula (II) and the corresponding known hydrazones of general formula (III).
  • Examples 2, 49 and 52 illustrate the preparation of compounds of general formula (I) which are in turn prepared by chemical transformation of the corresponding compounds of formula (I).
  • the reaction mixture was heated to reflux for 4 h, then it was poured onto ice, the pH was adjusted to 9 with conc. NH4OH and it was extracted with CH2Cl2. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo.
  • the crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively. The resulting solid was triturated in Et2O, yielding 0.15 g of the title product.

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Abstract

Substituted mono heterocycle-condensed morphinoid derivatives of formula (I) are potent and selective, delta opioid agonists and antagonists, and are of use as analgesics and for treating pathological conditions which, customarily, can be treated with agonists and antagonists of the delta opioid receptor. n = 0 or 1, X, Y, R1-R8 are as defined in the application.

Description

  • The present invention is concerned with novel morphinoid compounds, processes for their preparation and their use in medicine.
  • The presence of at least three populations of opioid receptors (mu, delta and kappa) is now well established and documented and all three appear to be present in the central and peripheral nervous system of many species including man (Lord J.A.H. et al., Nature 1977, 267, 495).
  • Activation of all three opioid receptor subtypes can lead to antinociception in animal models. In particular, studies with peptidic delta agonists have indicated that activation of the delta receptor produces antinociception in rodents, primates and can induce clinical analgesia in man (D. E. Moulin et al. Pain, 1985, 23, 213). Evidence exists that suggest a lesser propensity of delta agonists to cause the usual side-effects associated with mu and kappa activation (Galligan et al, J. Pharm. Exp. Ther., 1984, 229, 641).
  • P.S. Portoghese et al, J. Med. Chem, 1988, 31, 836-841, discloses binaltorphimine-related bivalent ligands and their kappa opioid receptor antagonist activity.
  • P.S. Portoghese et al, J. Med. Chem, 1991, 34, 1715-1720, discloses peptidomimetic delta-opioid receptor antagonists related to naltrindole.
  • US 5,223,507 and US 5,225,417 (G. D. Searle & Co.) disclose bicycle-condensed morphinoid compounds which are said to be delta opioid agonists having therapeutic utility as analgesics agents.
  • WO 94/07896 (Toray Ind. Inc.) discloses indole-condensed morphinoid compounds useful as immunosuppressants, anti-allergic and anti-inflammatory agents.
  • We have now discovered a novel class of substituted monoheterocycle-condensed morphinoid derivatives which are potent and selective delta opioid agonists and antagonists which may therefore be of potential therapeutic utility as analgesics, immunosuppressants to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agents, brain cell protectant, agents for treating drug and alcohol abuse, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy and, in general, for the treatment of those pathological conditions which customarily can be treated with agonists and antagonists of the delta opioid receptor.
  • According to the present invention, there is provided a compound, or a solvate or salt thereof of formula (I):
    Figure 00020001
    in which:
  • R1 is hydrogen, methyl, ethyl, propyl, i-propyl, allyl, benzyl, phenyl-ethyl, CH2CH2OH, CH2COOH, CH2COOEt, CH2CONH2, or COMe;
  • R2 is hydrogen, hydroxy or methoxy;
  • R3 is hydrogen, hydroxy, ethyl, bromine, hydroxy, methoxy, ethoxy, i-propoxy, COMe and OCH2COOH;
  • R4 and R5, which may be the same or different, are each independently hydrogen, hydroxy, C1-5 alkoxy, O-phenyl or together may form an oxy group (-O-); or R4 together with R3 may form a methylenedioxy group (-OCH2O-);
  • R6 is CONH2, CONMe2, CONEt2, CON(i-Pr)2, CON(i-Pr)CH2Ph, CON(i-Pr)(CH2)2OH, CON(CH2CF3)(i-Pr), COOMe, COOEt, COO-n-Pr, COO-i-Pr, COO-i-Bu, COOCH(i-Pr)2, CSNEt2, CSN(i-Pr)2, COOH, COMe, CO-i-Pr, CO-i-Bu, CO-t-Bu, CO-3-pentyl, COPh,
    Figure 00030001
    Figure 00030002
    or PO(OEt)2;
  • R7 is hydrogen, methyl or halogen-C1-2 alkyl;
  • R8 is hydrogen, C1-6 alkyl; and
  • Y is CH or a R6- or R7- substituted carbon atom.
  • Examples of R4 and R5 are hydrogen, hydroxy, acetyloxy, methoxy, O-phenyl, together as an oxy group or R4 together with R3 is a methylendioxy group.
  • An example of R8 is hydrogen.
  • Particularly preferred compounds of formula (I) are those in which R6 is CONEt2, CON(i-Pr)2 or COO-i-Bu, R7 is methyl, and R9 is hydrogen, methyl or CH2COOH.
  • The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.
  • Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • The compounds of formula (I) may exists in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.
  • The invention also provides a process for the preparation of a compound of formula (I), or a solvate or salt thereof, which comprises condensing a compound of formula (a), where K is H, Br, COR7, =CHOH or =NOH, with a compound of formula (b), where Q is COR7, CHClR7, COR7, SH or NH2, and J is =NNHPh, =O, =H2, or =CHR7 where R7 and R6 have the same meaning described above.
    Figure 00040001
    and optionally thereafter converting the compound of formula (I) to a solvate or salt thereof.
    Preferred reaction conditions when K = H, Q = COR7 and J = =NNHPh are AcOH/Zn in presence of AcONa at the temperature in a range of 60-100 °C;
    Preferred reaction conditions when K = COR7, Q = SH and J = =H2 are i) dry HCl in alcoholic media at RT, ii) strong base e.g. MeONa in MeOH.
    Preferred reaction conditions when K = H, Q = CHClR7 and J= =O are NaH in THF.
  • The compounds of formula (I), or salts or solvates thereof, may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing reactions not involving racemization processes or it may be prepared by chiral synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxy, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of diastereomeric salts by fractional crystallization and subsequent recovery of the pure enantiomers.
  • Compounds (I) in which n = 0, X = NH and Y is a R7-substituted carbon atom, may be obtained starting from ketones of formula (II) and hydrazones of formula (III) (Organic Reactions, 1959, 3-142) , in the presence of Zn and CH3COONa in CH3COOH as solvent (Khimiya GeteroL Soed., 1972, 342) as described in scheme 1:
    Figure 00050001
    Compounds (I) in which n = 0, X = NH and Y is a R6-substituted carbon atom, may be obtained by cyclization of halogeno ketones of formula (IV) (J. Org. Chem, 1964, 29, 3459), with ketones of formula (V) in the presence of NH4OH (Can. J. Chem., 1970, 48, 1689) as described in scheme 2:
    Figure 00050002
    Compounds (I) in which n = 0, X = O and Y is a R7-substituted carbon atom, may be obtained by cyclising ketones of formula (II) with α-halogenoketones (preferably α-chloroketones) of formula (VI), in the presence of a base (J. Org. Chem., 1984, 49, 2317) as described in scheme 3:
    Figure 00060001
    Compounds (I) in which n = 0, X = O and Y is a R6-substituted carbon atom, may be obtained by cyclization of the bromoketones (IV) with ketones (V) in ethanol in the presence of a base (preferably EtONa) (J. Chem. Soc. Perkin I, 1972, 2372) as described in scheme 4:
    Figure 00060002
    Compounds (I) in which n = 0, X = S and Y is a R7-substituted carbon atom, may be prepared from β-diketones of general formula (VII) (synthesised by Claisen reaction, starting from ketones (II) and esters of formula R7-COOEt; J. Am. Chem. Soc., 1945, 67, 1510; J. Med. Chem. 1982, 25, 983) and mercapto derivatives of formula (VIII) in the presence of HCl (DE 1.088.507; C.A., 1962, 56, 456; Synthesis, 1992, 526) as described in scheme 5:
    Figure 00060003
    Compounds (I) in which n = 0, Y = S and X is a R6-substituted carbon atom, may be obtained by reacting α-mercaptoketones (IX) (which may be prepared starting from the bromoketones (IV) and H2S/KOH, J. Am. Chem. Soc., 1985, 107, 4175) with an alkyne derivative of formula (X), in a solvent such as DMSO, in the presence of a base such as t-BuOK (Chem Ber., 1964, 97, 2109) as described in scheme 6:
    Figure 00070001
    Compounds (I) in which n = 0, X and Y are both N, may be obtained from hydroxyimino derivatives (XV) and R6- R7-substituted imidoyl chlorides of formula (XVI) in basic media, and subsequent treatment of the intermediates with H+ in refluxing toluene (J. Org. Chem., 1993. 58, 7092) as described in the scheme 7:
    Figure 00070002
    Compounds (I) in which n = 1, X = N and Y = CH may be obtained by reacting α-hydroxymethylenketones (XI) (which may be prepared from ketones (II) by condensation with HCOOEt in the presence of a base; Org. Synth. Coll., 1963, 4, 536) with enamines (XII) (J. Ind. Chem. Soc., 1935, 12, 289) as described in scheme 8:
    Figure 00080001
    Compound (I) in which n = 1, and X = Y = N may be obtained starting from α-hydroxyiminoketones (XIII) (which may be prepared from ketones (II) and i-amylnitrite/t-BuOK as described in J. Med. Chem., 1991, 34, 1715) with ethanediamines (XIV) and subsequent aromatization of the intermediate in basic media (Chem. Ber., 1967, 100, 555) as described in scheme 9:
    Figure 00080002
    Compound of general formula (I') in which n = 0, X = NH and Y is a R6- or R7-substituted carbon atom may be converted using an alkylating agent R9Br in the presence of NaH in DMF to obtain other compounds of general formula (I) in which the pyrrole nitrogen is substituted with a R9 group as generally described in Scheme 10.
    Figure 00080003
  • Compound of general formula (I') in which R4 = OH and R5 = H may be prepared from known ketones of formula (II) according to the Schemes described above or, alternatively, from compounds of general formula (I) in which R4 and R5 together form an oxy group (-O-), by reaction with Zn in boiling MeOH/HCl or boiling AcOH as described in the Scheme 11.
    Figure 00090001
    Compounds (I) in which n = 0, X = S and Y = N, R6 is NR13R14 where R13 is (CH2)mCOR group where m = 0 and R14 is hydrogen, may be obtained by cyclization of the bromoketones (IV) with thiourea in i-PrOH in the presence of a base (preferably Na2CO3) (J. Chem. Soc., 1945, 455) and subsequent acylation of the resulting amine with the appropriate acyl chloride or with the corresponding carboxylic acid in presence of a coupling reagent such as DCC as described in Scheme 12:
    Figure 00090002
  • Compounds of general formula (I) in which R6 ia a group C(Z)R12, in which Z is sulphur may be prepared from compounds in which Z is oxygen by reaction with thiation agents such as Lawesson reagent
  • Compounds of general formula (I) in which R6 = CH2WA may be prepared from compounds of general formula (I) by conventional chemical reactions well known in literature of groups R6 such as esters amides, tioamides.
  • The compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from the appropriate solvent For example, hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • Also salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • In general compounds of formula (I) acting as selective delta receptor ligands may be useful as analgesics, immunosuppressants to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agents, brain cell protectant, for the treatment of drug and alcohol abuse, to decrease gastric secretion, for the treatment of diarrhoea, cardiovascular and respiratory diseases, cough and respiratory depression, mental illness, epileptic seizures and other neurologic disorders (herein after referred to as 'Conditions'). In particular, the activity of the compounds of formula (I) as delta agonists in standard tests indicates that they are of potential therapeutic utility as analgesic agents for the amelioration or elimination of pain.
  • Accordingly the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
  • The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Conditions.
  • Such a medicament, and a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the Conditions.
  • Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
  • The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns.
  • A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.
  • The present invention also provides a method for the treatment and/or prophylaxis of the Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • The activity of the compounds of the present invention as selective delta ligands is determined in radioligand binding assays as described below.
  • Mouse brain membranes were prepared as described by Kosterlitz (Br. J. Pharmacol., 1981, 73, 939.). The binding of the preferential delta ligand [3H]-[D-Ala2,D-Leu5]-enkephalin (DADLE) was evaluated at its KD concentration (1.3 nM) in presence of 40 nM of the unlabelled mu ligand [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO). The binding of the mu ligand [3H]-DAMGO (Eur. J. Pharmacol., 1989, 166, 213) and of the kappa ligand [3H]-U69593 (Excerpta Medica, 1990, 211) were carried out at 0.5 nM. The non-specific binding was determined in presence of naloxone (10 µM) for all tritiated ligands. Binding data were expressed as percentage of inhibition and fitted the following equation: f(x) = 100·X/(IC50 + X) where X are cold drug concentration values. The IC50 obtained were used to calculate the inhibitory constants (Ki) accordingly to the Cheng and Prusoff relation (Biochem. Pharmacol., 1973, 22, 3099).
  • The delta agonist/antagonist activity of the compounds of the present invention is determined in the cAMP bioassay in NG108-15 cell lines as described below.
  • NG 108-15 cell were grown at 37 °C in humidified atmosphere of 5% CO2 and 95% air in DMEM (without sodium pyruvate using 4500 mg/l glucose) supplemented with 10% foetal calf serum containing 2mM glutamine, 2% HATx50 supplement, 50 µg streptomycin and 50 I.U. penicillin per ml confluent cells were harvested with 1M EDTA in Ca/Mg-free phosphate-buffered saline with mechanical stirring. Medium was replaced every 2 day. One day before the experiment the cells were dispensed in 17 mm culture plate (about 10x106 cells/plate). After 1 day, the growth medium was removed and cells washed twice with a modified Krebs-Ringer medium buffered with hepes-NaOH 200 mM, pH 7.4, that contained (mmol/l): NaCl (125), KCl (5), KH2PO4 (0.4), MgSO4 and CaCl2 (1.2) NaHCO3 (25), glucose (12). Incubation medium was also including 1mM 3-isobuthyl-1-methylxantine (IBMX). Experiments were performed at room temperature. After incubation for 10 minutes to allow IBMX incorporation, NG108-15 cells were exposed to 1µM forskolin and the compound to be tested, for 10 minutes. The reaction was terminated by adding cold 0.4N HClO4. After 15 minutes, the cold surnatants were carefully collected and neutralised using 1M K2CO3. After an overnight incubation at 4 °C the tubes were centrifuged at 9000 rpm for 5 minutes and a 100 µl aliquot tested for cAMP content by using the commercially available 125I cAMP RIA kit (Amersham Inc.). The pellets from the original plates were dissolved in NaOH 0.5N and the protein content was determined with the method described by Bradfort (Anal. Biochem. 1976, 72, 248). The data were normalised to protein content.
  • The most potent compounds described in the present invention showed affinities for the delta receptor ranging from 0.5 to 200 nM with delta selectivity ranging from 20 to 1500 times in respect to the other opioid receptor types. These compounds displayed also potent delta agonist or antagonist properties in the cAMP inhibition bioassay. Selective delta agonists (antagonised by the selective delta antagonist naltrindole) displayed IC50s ranging from 1 to 500 nM. For example, the compound of Example 10 shows a Ki delta = 2.9 nM, Ki mu/Ki delta = 840 and Ki kappa/Ki delta = 600. The compound of Example 1 showed an agonist activity in the inhibition of forskolin-stimulated cAMP in NG108-15 cells (IC50= 15 nM) completely antagonised by the selective delta antagonist naltrindole (100 nM).
  • Mouse abdominal constriction (MAC) (Proc. Soc. Exp. Biol. Med., 1957, 95, 729), mouse tail-flick (MTF) (J. Pharm. Exp. Ther., 1941, 72, 74) and mouse tail-flick warm water (MTF-WW) (Life Sci., 1986, 39, 1795) were adopted to evaluate the antinociceptive efficacy of the compounds of the present invention.
  • The following preparations 1 to 7 illustrate the synthetic procedure to obtain new ketones of general formula (II) that, as such, form a part of the present invention. In particular 4,5-epoxy-17-methyl-3-vinylmorphinan-6-one, 4,5-epoxy-3-(1-ethoxyvinyl)-17-methylmorphinan-6-one, 4,5-epoxy-3-ethyl-17-methylmorphinan-6-one, 3-bromo-4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one and 3-bromo-4,5-epoxy-17-methylmorphinan-6-one are novel compounds and are utilised as starting materials to prepare the compounds of Examples 28, 30, 33, 35, 41, 52, 61 and 64. Other ketones used as starting materials are known in the literature. Preparation 8 illustrates the preparation of a new phosphonohydrazone of general formula (III) that was used as starting material to prepare the compound of Example 89. Example 1 illustrates the preparation of compounds of general formula (I) of the present invention starting from the corresponding ketones of general formula (II) and the corresponding known hydrazones of general formula (III). Examples 2, 49 and 52 illustrate the preparation of compounds of general formula (I) which are in turn prepared by chemical transformation of the corresponding compounds of formula (I). Example 105 describes the preparation of compounds of general formula (I) in which n = 0, X = S and Y is a substituted carbon atom. The Examples described herein are prepared according to the same procedures as described for Examples 1, 2, 49, 52 and 105.
    The compounds of the Examples 1 to 105 are summarised in the Chemical Table.
    General procedure for the preparation of compounds of general formula (II) in which R3 =CH=CH2 and C(OEt)=CH2.
    • PREPARATION 1 4,5-Epoxy-17-methyl-3-trifluoromethanesulfonyloxymorphinan-6-one
  • 5.5 g (19.3 mmol) of 4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one were dissolved in 20 ml of pyridine under a nitrogen atmosphere. The solution was cooled to 0°C and 3.56 ml (21.2 mmol) of trifluoromethanesulfonic anhydride were added dropwise. The solution was stirred for 5 min at 0°C and then allowed to warm to room temperature overnight. The reaction mixture was poured onto water and the aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4 and the solvent removed in vacuo. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively, yielding 6.26 g of the title product.
    N.M.R. 300 MHz (CDCl3): δ 7.0 (d, 1H), 6.7 (d, 1H), 4.7 (s, 1H), 3.2 (m, 1H), 3.1 (d, 1H), 2.7-2.3 (m, 8H), 2.1 (m, 2H), 1.9-1.7 (m, 2H), 1.3-1.1 (m, 1H).
    MS (TSP) m/z = 417.2 (M+)
    • PREPARATION 2 4,5-Epoxy-17-methyl-3-vinylmorphinan-6-one
  • 2 g (4.8 mmol) of 4,5-epoxy-17-methyl-3-trifluoromethanesulfonyloxymorphinan-6-one were dissolved, under a nitrogen atmosphere, in 25 ml of dimethylformamide, then 1.46 ml (5 mmol) of vinyltributyltin, 1.6 g (38.4 mmol) of LiCl, 0.337 g (0.48 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.5 g (1.9 mmol) of triphenylphosphine were added. The reaction mixture was heated to 100°C for 3 h , then it was poured onto water and the aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively, yielding 1.1 g of the title product.
    N.M.R. 300 MHz (CDCl3): δ 7.1 (d, 1H), 6.8-6.6 (m, 2H), 6.0 (d, 1H), 5.4 (d, 1H), 4.6 (s, 1H), 3.2-1.7 (m, 13H), 1.2 (m, 2H).
    MS (TSP) m/z = 295.1 (M+)
    • PREPARATION 3 4,5-Epoxy-3-(1-ethoxyvinyl)-17-methylmorphinan-6-one
  • 2.5 g (6.0 mmol) of 4,5-epoxy-17-methyl-3-trifluoromethanesulfonyloxymorphinan-6-one, 2.1 ml (6.2 mmol) of (1-ethoxyvinyl)tributyltin, 2 g (48 mmol) of LiCl, 0.42 g (0.6 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.63 g (2.4 mmol) of triphenylphosphine in 25 ml of dimethylformamide were treated as described in Preparation 2. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively, yielding 1.95 g of the title product.
    I.R. (KBr): 2932, 1728, 1674 cm-1.
    N.M.R. 300 MHz (CDCl3): δ 7.4 (d, 1H), 6.6 (d, 1H), 5.2 (s, 1H), 4.65 (s, 1H), 4.45 (s, 1H), 3.9 (q, 2H), 3.2-1.4 (m, 18H).
    MS (TSP) m/z = 339.1 (M+).
    • PREPARATION 4 4,5-Epoxy-3-ethyl-17-methylmorphinan-6-one
  • 1.2 g (4.06 mmol) of 4,5-epoxy-17-methyl-3-vinylmorphinan-6-one were dissolved in 150 ml of absolute EtOH. 1 g of 10% Pd on charcoal was added and the reaction mixture was hydrogenated in a Parr apparatus at 35 psi and at room temperature for 8 h. The catalyst was filtered off and the solvent was removed in vacuo, yielding 0.77 g of the title product.
    N.M.R. 300 MHz (CDCl3): δ 6.9 (d, 1H), 6.6 (d, 1H), 4.6 (s, 1H), 3.2-1.7 (m, 18H), 0.9 (m, 2H).
    MS (TSP) m/z = 297.1 (M+)
    General procedure for the preparation of compounds of general formula (II) in which R3 = Br
    • PREPARATION 5 3-Bromo-4,5-epoxy-17-methylmorphinan-6-ol
  • 3.1 g (11.4 mmol) of 4,5-epoxy-17-methylmorphinan-6-ol were dissolved in 150 ml of glacial acetic acid and 11.4 ml of a 1M solution of Br2 in AcOH were added dropwise. After 1 h, AcOH was removed in vacuo, the residue was taken up with water, the aqueous solution was brought to pH 7 with a saturated NaHCO3 solution and extracted with AcOEt. The organic phase was dried over Na2SO4, the solvent was removed in vacuo, yielding 3.6 g of the title product.
    I.R. (KBr): 3580, 2930, 1452 cm-1.
    N.M.R. 300 MHz (CDCl3): δ 7.2 (d, 1H), 6.6 (d, 1H), 4.6 (d, 1H), 4.0 (m, 1H), 3.1 (m, 1H), 2.9 (d, 1H), 2.5-1.5 (m, 12H), 1.1 (m, 1H).
    MS (TSP) m/z = 349.0 (M-1)
    • PREPARATION 6 3-Bromo-4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one
  • 1.1 g (3.8 mmol) of 4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one in 50 ml of glacial AcOH were treated with 3.8 ml of a 1M solution of Br2 in AcOH as described in Preparation 5, yielding 1.1 g of the title product.
    I.R. (KBr): 3348, 2910, 1738 cm-1.
    • PREPARATION 7 3-Bromo-4,5-epoxy-17-methylmorphinan-6-one
  • A solution of 1.6 ml of DMSO in 4.8 ml of CH2Cl2 was added slowly, under a nitrogen atmosphere and at -55°C, to a solution of 0.9 ml of oxalyl chloride in 21 ml of CH2Cl2. After 2 min. 3.6 g (10.3 mmol) of 3-bromo-4,5-epoxy-17-methylmorphinan-6-ol in 20 ml of CH2Cl2 were added, followed, after 15 min. by 6.6 ml of Et3N. The reaction mixture was allowed to warm up to room temperature in 2 h, then it was quenched with 50 ml of H2O. The phases were separated, the organic phase was dried over Na2SO4 and the solvent was removed in vacuo. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively, yielding 2.87 g of the title product.
    I.R. (KBr): 2940, 1716, 1446 cm-1.
    N.M.R. 300 MHz (CDCl3): δ 7.2 (d, 1H), 6.6 (d, 1H), 5.4 (s, 1H), 3.3 (m, 1H), 2.95 (d, 1H), 2.6-1.7 (m, 12H), 1.2 (m, 1H).
    MS (TSP) m/z = 347.0 (M-1)
    • PREPARATION 8 Diethyl-1-phenylhydrazono-2-oxopropylphosphonate
  • To a solution of 5.0 g (0.0257 mol) of diethyl(2-oxopropyl)phosphonate in 25 ml of ethanol/water 4:1, were added 7.1 g (0.0517 mol) of K2CO3 and 0.0257 mol of phenyldiazonium chloride at 0-10°C. The resulting suspension was stirred until the temperature reached the room temperature. Then 30 ml of water and ml 100 of CH2Cl2 were added. The organic layer was dried on Na2SO4 and evaporated in vacuo yielding 7 g of the title compound as red oil which was used as such in the subsequent step.
    C13H19N2O4P
    IR (neat): 3498, 1716, 1666, 1268, 1026 cm-1
    N.M.R. 300 MHz (CDCl3): 12.9 (bs, 1H); 7.5-7.0 (m, 5H), 4.2 (m, 4H); 2.3 (s, 3H); 1.5 (m, 6H).
    • EXAMPLE 1 [8R-(4bS*,8α,8aβ,12bβ)]-11-(N-Benzyl-N-isopropylaminocarbonyl)-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride
  • 0.65 g (2.17 mmoles) of 7,8-dihydrocodeinone hydrochloride, 2.2 g (6.51 mmoles) di N-benzyl-N-isopropyl-2-phenylhydrazone-3-oxobutiramide, were dissolved in a mixture of 10 ml di glacial acetic acid and 0.54 g (6.51 mmoles) of CH3COONa. The resulting reaction mixture was warmed to 60 °C, then 0.57 g (8.6 mmoles) of Zn dust were added portionwise and under nitrogen atmosphere. The mixture was refluxed for 2 h, and then cooled to room temperature. The resulting salts were eliminated by decantation and washed with acetic acid. The acidic solutions were collected and then brought to pH 8 and extracted several times with AcOEt. The organic phase was dried and evaporated to dryness in vacuo. The resulting residue was purified by medium pressure chromatography using silica gel (15-25 µ) and a mixture of AcOEt/MeOH/NH4OH conc. 90:10:0.5 as eluent. The product was taken up in a mixture of acetone/MeOH 1:1 and the solution was brought to acidic pH with HCl/Et2O. The resulting precipitate was filtered, washed and dried yielding 0.5 g of the title compound. M.P. = 304 °C dec.
    • EXAMPLE 2 [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminothiocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride
  • 1 g (2.3 mmoles) of [8R-(4bS*,8α,8aβ,12bβ)]-11-diethylaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline, 0.950 g (2.3 mmoles) of the Lawesson reagent, were dissolved in 40 ml of toulene and the mixture refluxed for 4 h. The solvent was removed in vacuo , then the residue was taken up in CH2Cl2 and washed with s.s. NaHCO3. The organic layer was dried on Na2SO4. After evaporation of the solvent, the residue was purified with flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH conc. 86:10:0.6) then the product was dissolved in acetone. The resulting solution was brought to acidic pH with HCl/Et2O. The precipitate was filtered, dissolved in boiling MeOH in presence of charcoal for 30'. The charcoal was filtered off, and the solution was evaporated to dryness. The residue was triturated with boiling Et2O yielding 0.41 g of the title compound. M.P. > 250 °C.
    The compound of Example 73 was prepared according to the same procedure described above.
    • EXAMPLE 49 [8R-(4bS*,8α,8aβ,12bβ)]-11-Isopropylcarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g] isoquinoline hydrochloride
  • 0.52 g (1.2 mmoles) of [8R-(4bS*,8α,8aβ,12bβ)]-11-isopropylcarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline (Example 34) were dissolved in 5 ml of DMF under nitrogen atmosphere. 0.051 g of 60% NaH was added portionwise maintaing the temperature of 0° C. After 30' a solution of 0.2 g of MeI dissolved in 1 ml of DMF was added dropwise. The reaction was quenched after 1 h with using crushed ice. The resulting solution was exhaustively with Et2O. The organic layers were dried over Na2SO4 and then the solvent in vacuo. The resulting residue was dissolved in acetone and the solution brought to acidic pH with Et2O/HCl. The solvent was in turn evaporated and the resulting residue was triturated with boiling Et2O. The solid was filtered, washed and dried to yield 0.25 g of the title compound. M.P. 240-243 °C.
    The compounds of Examples 62 and 82 were prepared according to the procedure described above.
    The compounds of Examples 74, 79 and 80 were prepared following the same procedure using as alkylating agent ethylbromoacetate. The resulting ethylesters were in turn hydrolysed in acidic conditions to the corresponding acid derivatives of the above Examples.
    • EXAMPLE 52 [10R,4bS-(4bb, 9ab)]-3-Bromo-7-diisopropylaminocarbonyl-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-4-hydroxy-(6H)-10,4b-(iminoethano)phenanthro [3,2-b]pyrrole
  • 0.3 g (0.58 mmol) of [8R-(4bS*,8a,8ab,12bb)]-1-bromo-11-diisopropylamino carbonyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline (Example 30) were dissolved, under a nitrogen atmosphere, in 10 ml of glacial AcOH and 0.15 g (1.8 mmol) of AcONa were added. The reaction mixture was heated to 80°C and 0.23 g (3.5 mmol) of Zn dust were added portionwise. The reaction mixture was heated to reflux for 4 h, then it was poured onto ice, the pH was adjusted to 9 with conc. NH4OH and it was extracted with CH2Cl2. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively. The resulting solid was triturated in Et2O, yielding 0.15 g of the title product.
    • EXAMPLE 105 [8R-(4bS*,8α,8aβ,12bβ)]-11-Methoxycarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,9,12b-hexahydro-4,8-methanobenzofuro [3,2-e]thieno[2,3-g]isoquinoline hydrochloride
  • A solution of 7-acetyl-4,5-epoxy-1-methoxy-17-methylmorphinan-6-one (1g, 2.9 mmol.) (J. Med. Chem. 1982, 25, 983) in MeOH (40 mL) was cooled at -10 °C and a stream of dry HCl was bubbled into the system until saturation (∼1h.). Then, thioglycolic acid (0.4 mL, 5.8 mmol) was added, and the bubbling of HCl was continued at -10 °C for 4 h. The mixture was left at RT for 6 days. The solvent was evaporated in vacuo, the residue treated with conc. NH4OH and extracted with AcOEt. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The crude product was directly used in the next step.
    A 2N solution of MeONa (10 ml) was added to a solution of the above product in 12 ml MeOH was added and kept under nitrogen for 24 h. The solvent was evaporated and the residue treated with ice-cold water. The mixture was acidified with 6N HCl to pH = 1. After washing with AcOEt the aqueous layer was treated with NaOH to pH = 9 and extracted with AcOEt. The solvent was dried, evaporated and the crude product was purified by silica gel chromatography (CH2Cl2/MeOH/conc. NH4OH; 95:5:0.5). The resulting product was treated with HCl/Et2O yielding 55 mg of the title compound.
    Figure 00190001
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    Figure 00230001
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    Figure 00250001
    Figure 00260001
    Figure 00270001
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    Figure 00290001
    Figure 00300001
    Figure 00310001
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    Figure 00370001
    Figure 00380001
    Figure 00390001
    Figure 00400001
    Figure 00410001

Claims (8)

  1. A compound, or a solvate or salt thereof, of formula (I):
    Figure 00420001
    in which,
    R1 is hydrogen, methyl, ethyl, propyl, i-propyl, allyl, benzyl, phenyl-ethyl, CH2CH2OH, CH2COOH, CH2COOEt, CH2CONH2 or COMe;
    R2 is hydrogen, hydroxy or methoxy;
    R3 is hydrogen, hydroxy, ethyl, bromine, methoxy, ethoxy, i-propoxy, COMe, or OCH2COOH;
    R4 and R5, which may be the same or different, are each independently hydrogen, hydroxy, C1-5 alkoxy, O-phenyl or together may form an oxy group (-O-); or R4 together with R3 may form a methylendioxy group (-OCH2O-);
    R6 is CONH2, CONMe2, CONEt2, CON(i-Pr)2, CON(i-Pr)CH2Ph, CON(i-Pr)(CH2)2OH, CON(CH2CF3)(i-Pr), COOMe, COOEt, COO-n-Pr, COO-i-Pr, COO-i-Bu, COOCH(i-Pr)2, CSNEt2, CSN(i-Pr)2, COOH, COMe, CO-i-Pr, CO-i-Bu, CO-t-Bu, CO-3-pentyl, COPh,
    Figure 00420002
    Figure 00420003
    or PO(OEt)2;
    R7 is methyl or halogen-C1-2alkyl;
    R8 is hydrogen or C1-6 alkyl; and
    Y is CH or a R6- or R7-substituted carbon atom.
  2. A compound according to claim 1 in which R4 and R5 are each hydrogen, hydroxy, acetyloxy, methoxy, O-phenyl, or together form an oxy group, or R4 together with R3 is a methylendioxy group.
  3. A compound selected from the list consisting of:
    [8R-(4bS*,8α,8aβ,12bβ)]-11-(N-Benzyl-N-isopropylaminocarbonyl)-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylamminothiocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [10R, 4bS-(4bβ, 9aβ)]-7-Diethylaminocarbonyl-8,14-dimethyl-4-hydroxy-4b,5,9,9a,10,11,-hexahydro-(6H)-[2,3-h]pyrrolo[10,4-b]iminophenantrene;
    [10R-4bS-(4bβ,9aβ)]-7-Diethylaminocarbonyl-3,4-dimethoxy-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-(6H)-[2,3-h]pyrrolo[10,4-b]iminophenantrene hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminocarbonyl-1,8a-dimethoxy-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methano benzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-11-ethoxycarbonyl-5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminocarbonyl-8a-hydroxy-1-methoxy-10-methyl-7-(2-propenyl)-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [10R-4bS-(4bβ, 9aβ)]-7-Diethylaminocarbonyl-8,14-dimethyl-3-methoxy-4-oxyphenyl-4b,5,9,9a,10,11-hexahydro -(6H)-[2,3-h]pyrrolo[10,4-b]-iminophenantrene;
    [10R-4bS-(4bβ, 9aβ)]-7-Diethylaminocarbonyl-8,14-dimethyl-3-methoxy-4b,5,9,9,a,10,11-hexahydro -(6H)-[2,3-h]pyrrolo[10,4b]iminophenantrene;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Ethoxycarbonyl-7-methyl-1-methoxy-10-trifluoromethyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Ethoxycarbonyl-7-methyl-10-(1-methylethyl)-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylcarbonyl-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Benzoyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g] isoquinoline-11-carboxy acid;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-diethylaminocarbonyl-1-methoxy-10-methyl-7-(2-phenylethyl)-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminocarbonyl-7-ethyl-10-methyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo [2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Acetyl-7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Isobutylcarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydra-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Benzyl-11-diethylaminocarbonyl-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminocarbonyl-7-isopropyl-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminocarbonyl-10-methyl-1-methoxy-7-isopropyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7,10-dimethyl-1-ethoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7,10-dimethyl-1-isopropyloxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7-methyl-1-methoxy- 10-trifluoromethyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobutylcarbonyl-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g] isoquinoline-(9H)-8a-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobutylcarbonyl-10-methyl-5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g] isoquinoline-1,8a(9H)-diol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobutylcarbonyl-1-ethoxy-10-methyl-5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g] isoquinoline-(9H)-8a-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7,10-dimethyl-1-ethyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11(3-methyl-1,2,4-oxadiazole-5-yl)-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-11-diisopropylaminocarbonyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo-[2,3-g]isoquinolin-8a-(9H)-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Ethoxycarbonyl-10-ethoxycarbonyl methylen-1-methoxy-7-methyl -5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e] pyrrolo [2,3-g]isoquinolin-8a-(9H)-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-11-tertbutylcarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-11-diisopropylaminocarbonyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-isopropylcarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-7,10-dimethyl-11-isobutylcarbonyl-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [10R,4bS-(4bβ,9aα)]-7diisopropylaminocarbonyl-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano)phenantro[3,2-b]pyrrole;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-11-(2-propyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-11-(1,1-dimethylethyl)oxycarbonyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]-pyrrolo [2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-11-methoxycarbonyl-1-methoxy-11-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-11-(1-propyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-Acetyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]-11-isobutylcarbonyl-4,8-methanobenzofuro[3,2-e]pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Ethyloxayl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo-[2,3-g] isoquinoline hydrochloride;
    [10R,4bS-(4bβ,9aα)]-7-Isobutylcarbonyl-8,14-dimethyl-4-hydroxy-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano) phenantro[3,2-b]pyrrole hydrochloride;
    [10R,4bS-(4bβ,9aα)]-14-Allyl-7-isobutylcarbonyl-4-hydroxy-8-methyl-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano) phenantro-[3,2-b]pyrrole-9a-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobutylcarbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]-isoquinoline hydrochloride;
    [10R,4bS-(4bβ,9aα)]-4-Acetoxy-7-diisopropylaminocarbonyl-8,14, dimethyl-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano)phenantro-[3,2-b]pyrrole;
    [10R,4bS-(4bβ,9aα)]-14-Allyl-7-isobutylcarbonyl-8-methyl-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano) phenantro[3,2-b]pyrrole-9a-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-11-(pentyl-3-carbonyl)- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]-isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Isopropylcarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]-isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7,10-dimethyl- 1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]-pyrrolo[2,3-g]isoquinoline-8a-(9H)-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10,11-trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-3-Bromo-7-diisopropylaminocarbonyl-8,14-dimethyl-1-methoxy-4b,5,9,9a,10,11-hexahydro-4-hydroxy-[6H]-10,4b-(iminoethano)phenantro[3,2-b]pyrrole;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-isopropylethanolaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e]pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-disopropylaminocarbonyl-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-isobutylcarbonyl-3-methoxy-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-4-hydroxy[6H]-10,4b-(iminoethano)phenantro-[3,2-b]pyrrole;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7-hydroxyethyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e] pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-carboxamido-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro [3,2-e]pyrrolo[2,3-g]-isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-(N-Benzyl-N-isopropyl)amino carbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro-[3,2-e]pyrrolo[2,3-g] isoquinoline-8a-(9H)-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Isopropylethanoaminocarbonyl-8,14-dimethyl-4-hydroxy-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-[2,3-h]pyrrolo-[10,4b]-iminoethanophenantrene;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Benzoyloxycarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro [3,2-e] pyrrolo-[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-Acetyl-7,10-dimethyl- 5,6,7,8,12,12b-hexahydro-[9H]-11-(2-methylpropyl)oxycarbonyl- 4,8-methanobenzofuro [3,2-e]-pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]-pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-(2,4-dimethyl-3-pentyloxy)carbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro [3,2-e]-pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-7,10-dimethyl- 5,6,7,8,12,12b-hexahydro-[9H]-11-(2-methylpropyl)oxycarbonyl 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline;
    [10R-4bS-(4bβ,9aβ)]-8,10-Dimethyl-4b,5,9,9a,10,11-hexahydro-[9H]-7-(2-methylpropyl)oxycarbonyl-10,4b-(iminoethano)phenantro [3,2-b] pyrrole hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Ethoxycarbonylmethylen-11-diisopropylaminocarbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Oxycarbonylmethylen-11-diisopropylaminocarbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e] pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-11-dimethylamino carbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro-[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride;
    [10R-4bS-(4bβ,9aβ)]-8,14-Dimethyl-7-isobutyloxycarbonyl-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-[2,3-h]pyrrolo [10,4b]-iminoethanophenantrene hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-11-(2-methylpropyl)oxycarbonyl-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-1-methoxy-7-methyl-10-oxycarbonyl-11-oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ]-7-Aminocarbonylmethyl-11-diisopropylaminocarbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ]-11-diisopropylaminothiocarbonyl-1-methoxy-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline;
    [[8R-(4bS*,8α,8aβ,12bβ]-7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetic acid hydrochloride;
    [10R,4bS-(4bβ,9aβ)]-7-Diisopropylaminocarbonyl-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-9a-hydroxy-[6H]-10,4b-(iminoethano)phenantro [3,2-b]pyrrole;
    [10R,4bS-(4bβ,9aβ)]-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-9a-hydroxy-7-(2-methylpropyl)oxycarbonyl-10,4b-(iminoethano)phenantro[3,2-b] pyrrole hydrochloride;
    [10R,4bS-(4bβ,9aβ)]-14-Allyl-7-diisopropylcarbonyl-4b,5,9,9a,10,11-hexahydro-9a-hydroxy-10,4b-(iminoethano) phenantro [3,2-b] pyrrole hydrochlorid
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-diisopropylaminothiocarbonyl-1-ethoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] -pyrrolo[2,3-g]isoquinolin-8a-ol hydrochloride;
    [[8R-(4bS*,8α,8aβ,12bβ)]-11-diisopropylaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetic acid hydrochloride;
    [[8R-(4bS*,8α,8aβ,12bβ)]-11-(N-Benzyl-N-isopropyl) amino carbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro-[3,2-e]pyrrolo[2,3-g] isoquinolin-12-yl] acetic acid hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-(2-methylpropyl)oxy carbonyl-1-ethoxy- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methano benzofuro [3,2-e] pyrrolo[2,3-g]-isoquinolin-8a-ol hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10,12-trimethyl-1-methoxy-11-methyloxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]pyrrolo[2,3-g]-isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-7-acetoxy-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]-pyrrolo[2,3-g] isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Diisopropylaminocarbonyl-4,8-diacetoxy-14-methyl-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-[2,3-h]pyrrolo[10,11-b]-iminoethanophenantrene;
    Ethyl-[[8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano-benzofuro [3,2-e] pyrrolo[2,3-g] isoquinolin-12-yl] acetate hydrochloride;
    N-Benzyl-[[8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11-(2-methylpropyl) oxycarbonyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methano-benzofuro[3,2-e]pyrrolo[2,3-g]isoquinolin-12-yl] acetamide hydrochloride;
    Ethyl-[[8R-(4bS*,8α,8aβ,12bβ)]-11-diisopropylaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]-pyrrolo[2,3-g]isoquinolin-12-yl] acetate;
    Ethyl-[8R-(4bS*,8α,8aβ,12bβ)]-11-isobutylcarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline;
    Ethyl-[8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylphosphonoyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-[(2,2,2-trifluoroethyl)-isopropylamino]carbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano-benzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-10-methyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano-benzofuro [3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-hydroxy-11-(2-methylpropyl)oxycarbonyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methano-benzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [[8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-(2-methylpropyl)oxycarbonyl-8a-hydroxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]-pyrrolo[2,3-g](1-isoquinolinyloxy)]acetic acid;
    N-Methyl-[8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1methoxy-11-(methylpropyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinolin-12-yl]acetamide hydrochloride;
    N,N-Dimethyl-[8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1methoxy-11-(methylpropyl)oxycarbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl]acetamide hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1methoxy-11-(pyrrolidin-1-yl)carbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1methoxy-11-(piperidin-1-yl)carbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1methoxy-11-(morpholi-4-yl)carbonyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11-(4-methyl-piperazin-1-yl)carbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11-(4-(2-hydroxyethyl)-(piperazin-1-yl)carbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano-benzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline dihydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-11-[N-(4-ethoxycarbonyl)-phenylmethyl-N-isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11-[N-(4-carboxy)-phenylmethyl-N-isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11-[N-(3-ethoxycarbonyl)-phenylmethyl-N-isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride;
    [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-[N-(3-carboxy)-phenylmethyl-N-isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride, and;
    [8R-(4bS*,8α,8aβ,12bβ)]-11-Methoxycarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,9,12b-hexahydro-4,8-methanobenzofuro [3,2-e]thieno[2,3-g]isoquinoline hydrochloride.
  4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
  5. A compound according to any one of claims 1 to 3 for use as an active therapeutic substance.
  6. A compound according to any one of claims 1 to 3 for use as an analgesic, immunosuppressant to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agent, brain cell protectant, for the treatment of drug and alcohol abuse, to decrease gastric secretion, for the treatment of diarrhoea, cardiovascular and respiratory diseases, cough and respiratory depression, mental illness, epileptic seizures and other neurologic disorders.
  7. The use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for use as an analgesic, immunosuppressant to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agent, brain cell protectant, for the treatment of drug and alcohol abuse, to decrease gastric secretion, for the treatment of diarrhoea, cardiovascular and respiratory diseases, cough and respiratory depression, mental illness, epileptic seizures and other neurologic disorders.
  8. A process for the preparation of a compound of formula (I) as defined in claim 1 or a solvate or salt thereof, which comprises condensing a compound of formula (a), where K is H, Br, COR7, =CHOH or =NOH, with a compound of formula (b), where Q is COR7, CHClR7, COR7, SH or NH2, and J is =NNHPh, =O, =H2, or =CHR7 where R7 and R6 are as defined in claim 1
    Figure 00510001
    and optionally thereafter converting the compound of formula (I) to a solvate or salt thereof.
EP97901009A 1996-01-10 1997-01-08 Heterocycle-condensed morphinoid derivatives (ii) Expired - Lifetime EP0880526B1 (en)

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ITMI960029 1996-01-10
IT96MI000029 IT1282950B1 (en) 1996-01-10 1996-01-10 New fused poly:hydro-imino:ethano-phenanthrene derivatives - useful as delta opioid agonists or antagonists having e.g. analgesic, antiallergic anti-inflammatory or immunosuppressant activity
ITMI962291 1996-11-05
IT96MI002291 IT1287130B1 (en) 1996-11-05 1996-11-05 New fused poly:hydro-imino:ethano-phenanthrene derivatives - useful as delta opioid agonists or antagonists having e.g. analgesic, antiallergic anti-inflammatory or immunosuppressant activity
PCT/EP1997/000120 WO1997025331A1 (en) 1996-01-10 1997-01-08 Heterocycle-condensed morphinoid derivatives (ii)

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